Interaction of haloperidol and ?-butyrolactone with (+)-amphetamine-induced changes in monoamine synthesis and metabolism in rat brain

Abstract

The interaction of (+)-amphetamine with haloperidol andγ-butyrolactone on synthesis of monoamines in rat brain regions was investigated using anin vivo method, in which the accumulation of dopa and 5-hydroxytryptophan (5-HTP) was measured after inhibition of the aromatic amino acid decarboxylase by means of 3-hydroxybenzylhydrazine. The accumulation of 3-methoxytyramine (3-MT) after inhibition of the monoamine oxidase with pargyline was taken as an indicator of thein vivo release of dopamine (DA) into the extraneuronal space. (+)-Amphetamine at doses of 1-3 mg/kg caused an increase of dopa formation in the DA-rich areas c. striatum and mesolimbic forebrain but had no effect on dopa formation in neocortex and 5-HTP formation in all brain regions investigated. At a dose of 10 mg/kg (+)-amphetamine decreased dopa as well as 5-HTP formation in all brain regions studied. 3-MT accumulation in whole rat brain was stimulated by (+)-amphetamine as well as haloperidol and inhibited byγ-butyrolactone. Combined treatment with haloperidol and (+)-amphetamine not only potentiated the stimulation of dopa formation but also the increase of 3-MT accumulation. Pretreatment withγ-butyrolactone antagonized the stimulation of 3-MT formation induced by (+)-amphetamine at a dose of 10 mg/kg. This dose of (+)-amphetamine markedly counteracted theγ-butyroiactoneinduced increase in dopa formation especially in the DA-rich areas. The data support the view that impulse flow in DA neurons facilitates the effect of (+)-amphetamine on DA release and DA synthesis. Inhibition of catecholamine synthesis after high doses of (+)-amphetamine may be due to an increase in cytoplasmatic DA concentration causing end-product inhibition of tyrosine hydroxylase.